Cisplatin--cis-diamine-dichloroplatinum (II)--is one of the more effective anti-tumor agents used in the systemic treatment of germ cell cancers. This chemotherapeutic drug is highly effective in the treatment of tumor models in laboratory animals and in human tumors, such as endometrial, bladder, ovarian and testicular neoplasms, as well as squamous cell carcinoma of the head and neck (Sur, et al., 1983; Steerenberg, et al., 1987).
Like other cancer chemotherapeutic agents, cisplatin is a highly toxic drug. The main disadvantages of cisplatin are its extreme nephrotoxicity, which is the main dose-limiting factor, its rapid excretion via the kidneys, with a circulation half life of only a few minutes, and its strong affinity to plasma proteins (Freise, et al., 1982).
Attempts to minimize the toxicity of the drug have included combination chemotherapy, synthesis of cisplatin analogues (Prestayko, 1991; Weiss, et al., 1993), immunotherapy and entrapment in liposomes (Sur, et al., 1983; Weiss, et al., 1993). Antineoplastic agents, including cisplatin, entrapped in liposomes have a reduced toxicity, relative to the agent in free form, while retaining antitumor activity (Steerenberg, et al., 1987; Weiss, et al., 1993).
Cisplatin, however, is difficult to efficiently entrap in liposomes because of the drug's low aqueous solubility, approximately 1.0 mg/ml at room temperature, and low lipophilicity, both of which contribute to a low drug/lipid ratio.
Liposomes containing cisplatin suffer from another problem--stability of the composition. In particular, maintenance of drug potency and retention of the drug in the liposome during storage are recognized problems (Freise, et al., 1982; Gondal, et al., 1993; Potkul, et al., 1991; Steerenberg, et al., 1987; Weiss, et al., 1993) and a limited shelf life of liposomes containing cisplatin, on the order of several weeks at 4.degree. C., has been reported (Gondal, et al., 1993; Potkul, et al., 1991).